The invention relates to 2',5'-oligoadenylates which possess a cyclophosphate group at the 3' end and a free OH group at the 5' end, to a process for preparing these compounds, to a pharmaceutical preparation comprising them, and to the use of these compounds for treating external papillomatoses.
The invention relates to novel chemical compounds, specifically 2',5'-oligoadenylate-2',3'-cyclophosphates of the general formula ##STR2## in which 0.ltoreq.n .ltoreq.10, in particular from .gtoreq.0 to 10, preferably 1 or 2.
The compounds in which n=1 or 2, in particular, may advantageously be used for medicinal purposes, specifically for the topical treatment of dermal and epithelial lesions which are caused by papilloma viruses.
Papillomatoses which are caused by papilloma viruses of the Papovaviridae family are infectious diseases which are widely distributed in humans and animals. Currently, more than 60 types of human papilloma viruses are known.
All these viruses possess a similar structure. In each case, their genome consists of a double-stranded, covalently closed annular DNA of 8000 base pairs which encodes the virion proteins and the proteins which are required for the intercellular development of the virus. In the infected cell, the papilloma virus genome is replicated over many generations in the form of episomes (dozens of copies per cell). Mature virions are only formed in the cells at the final stage of differentiation.
Under persistent conditions, it is only the first genes of the papilloma virus genome which are expressed, with these genes causing an alteration in the cell phenotype and in this way leading to the formation of papillomatoses. In the infected cells, a particular moiety of the virus genome has a probability, which is dependent on the virus type and on other factors, of being able to be incorporated into the cell genome, something which can then trigger conversion to malignancy. It is known that a substantial number of human tumors are the result of the conversion of papillomatoses to malignancy. These tumors thus represent a consequence of persistent, latent viral infections.
In this context, anogenital papillomatoses which are transferred by the sexual route are the most dangerous as far as conversion to malignancy is concerned (see M. Spitzer, Obstet. Gynecol., 1989, vol. 73, N3, pp. 303-307; H. zur Hausen, A. Schneider, The Role of Papilloma viruses in Human Anogenital Cancer, in: The apapovaviridae (N. P. Alzman ed.), 1987, vol. 2, pp. 245-263; H. zur Hausen, Papilloma viruses as Carcinomaviruses, in: Adv. in Virus Oncology (G. Klein ed.), 1989, vol. 8, pp. 1-26).
Since papillomatoses are precancerous disorders which are easy to diagnose, the development of many tumors can be prevented by treating benign papillomatoses, i.e. before malignant conversion of the infected cells takes place.
At present, the most important methods for treating papillomatoses are surgical removal of the papillomas and necrotization by means of electrocauterization, cryocauterization or laser cauterization (see Virus infections. Etiology, epidemiology, clinics, pathogenesis and diagnosis. Rep. Col. of Scient. Public., Sverdlovsk, 1985 (in Russian)). For this purpose, use is made of liquid oxygen, and acids and mixtures thereof (nitric acid, oxalic acid, lactic acid, etc.), which bring about necrosis of the surrounding healthy tissue and, at the application site, lead to scar formation and frequently to recurrences and to the appearance of new papillomas close to the site from which the old ones were removed (see S. A. Bashi, Cryoterapia versus podophyllin in the treatment of genital warts, Int. J. Dermatol., 1985, vol. 24, N 8, pp. 535-536).
The effectiveness of medicinal methods for treating papillomatoses using podophyllotoxin and interferon is low and is also associated with powerful side effects and/or after-effects, even when therapeutic doses are used.
The biological activity of podophyllin can be explained by its antimitotic effect, which is comparable to that of colchicin. Its use frequently causes local reactions (inflammations, allergic contact dermatoses, occasional skin erosions, etc.) and also undesirable after-effects such as peripheral neuropathy, tachypnea, hematuria and spontaneous abortion (see K. R. Beutner, Podophyllotoxin in the treatment of genital human papilloma virus infections. Seminars in Dermatology, 1987, vol. 6, NI, pp. 10-18).
In the case of papillomatoses, the administration of interferon has only a slight effect, and the doses which are employed for this treatment can lead to suppression of the immune system and to the triggering of autoimmune disorders (see F. G. Bruins, A. J. C, von don Brule, R. Mullnik, G. M. M. Walboomers, C. J. Meijer, R. Willemze, J. Invest. Dermatol., 1989, vol. 93, N4, pp. 544-545; M. Foldvan, A. Moreland, M. Nezei, ibid., pp. 550; G. Gross, Roussaki, ibid., pp. 553; M. Niimura, imbid., pp. 567).
Synthetic analogs of 2',5'-oligoadenylates (2,5 A) are known for the fact that they exhibit immunosuppressant activity and have previously been proposed for use in surgical transplantation. It has been established that oligoadenylates are less toxic, more specifically active and more effective, as mediators of the effects caused by interferon, than are immunosuppressants (see A. Kimchi et al., U.S. Pat. No. 4,378,352 (1983)).
The same effect is also achieved by a synthetic 2,5 A which contains a terminal morpholine group (see R. Torrence et al., U.S. Pat. No. 4,515,781 (1985)).
2,5 A analogs which possess at least three adenosine fragments are known to be active inhibitors of viral protein synthesis in vitro (see Jan M. Kerr et al., U.S. Pat. No. 4,21,P,746 (1980)).
While some synthetic analogs of 2,5 A-oligo-3'-deoxyadenylates and their derivatives inhibit the infection and transformation of animal cells with herpes simplex and Epstein-Barr viruses, in particular in in-vitro cultures, they are nevertheless inactive in the case of cells which are already infected or transformed (see R. I. Suhadolnik et al., U.S. Pat. No. 4,464,359 (1984); R. I. Suhadolnik et al., U.S. Pat. No. 4,539,313 (1985); R. I. Suhadolnik et al., U.S. Pat. No. 4,708,935 (1987)).
It is possible to use 2,5 A for treating infectious diseases which are caused by cytomegalovirus, hepatitis B virus and varicella zoster viruses (see European Patent Application No. 121 635 (Au, No. J, Dk, Fi, Fr, Es), 1984).